Farrell sustained an ankle problem during Saturday's 32-15 win over Australia, while fellow Saracens player George suffered a knee issue in that game.
Jack Singleton and his uncapped Gloucester teammate Harry Elrington have been called up by head coach Eddie Jones ahead of next Saturday's Twickenham clash with the Springboks.
Meanwhile, Joe Marler will join the group on Friday after completing his 10-day isolation period following a positive coronavirus test result.
England are preparing to meet South Africa for the first time since suffering a 32-12 defeat in the final of the 2019 World Cup in Yokohama.
Head coach Jones has named a 34-man squad for the game, which rounds off his side’s autumn campaign following consecutive wins over Tonga and the Wallabies.
Front-rower Singleton, 25, returns to the international fold having won three caps in 2019, including a substitute appearance against the United States during the World Cup pool stage.
Loosehead prop Elrington, 27, joined Gloucester ahead of the current season having begun his career with London Irish.
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